Signaling mechanisms linking infection, endocrine dysfunction, and growth failure

与感染、内分泌功能障碍和生长障碍相关的信号机制

基本信息

批准号：
10524772
负责人：
Michelle L Bland
金额：
$ 40.38万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-15 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10524772
关键词：
Address Animals Binding Campylobacter Campylobacter infection Campylobacter jejuni ChIP-seq Child Childhood Chronic Chronic Childhood Arthritis Complication Crohn&apos s disease Cytokine Signaling Data Diarrhea Disease Drosophila genus Drosophila melanogaster Endocrine Endocrine disruption Endotoxins Escherichia coli Event Exhibits Failure Fat Body Functional disorder Genes Genetic Genetic Models Genetic Screening Genetic Transcription Genomic approach Genomics Growth Growth Hormone Signaling Pathway Hepatocyte Heterozygote Homologous Gene Hormones Immune Immune response Immune signaling Impaired cognition Impairment Infection Inflammation Inflammatory Inflammatory Bowel Diseases Innate Immune System Insulin-Like Growth Factor I Interleukins Laboratories Larva Learning Disabilities Link Liver Mammals Messenger RNA Molecular Mus Mutation NF-kappa B Organ Orthologous Gene Pathway interactions Patients Prevention Principal Investigator Production Receptor Signaling Regulation Shigella Signal Pathway Signal Transduction Site Somatotropin TLR4 gene Tissues Toll-like receptors Transcript Work chronic infection cognitive development cognitive function cognitive performance cytokine early childhood enteric infection enteric pathogen fly forward genetics gastrointestinal genetic approach hormonal signals hormone regulation hormone resistance in vivo innate immune function insulin-like peptide loss of function mutation model organism novel therapeutics pathogen pharmacologic postnatal promoter rapid growth receptor recruit response stem transcriptomics whole genome

项目摘要

Infections and inflammatory diseases during childhood cause growth failure. Chronic and simultaneous infection with multiple enteropathogens such as Campylobacter spp. and Escherichia coli is a regular aspect of childhood in many parts of the world. Children suffering from these infections, even when they are asymptomatic for diarrhea, exhibit reduced linear growth. Similarly, children with inflammatory diseases such as juvenile idiopathic arthritis or Crohn's disease are smaller than healthy children. Reduced childhood growth is linked to impaired cognitive function, a complication seen in children with chronic enteropathogen infections and in patients with loss-of-function mutations in the insulin-like growth factor-1 (Igf1) gene. Childhood infections and inflammatory diseases that lead to growth failure are associated with low IGF-1 and elevated growth hormone (GH) levels, indicating GH resistance. However, the signaling events that lead to GH resistance in response to infection and inflammation are not understood. The principal investigator's laboratory recently made the discovery that activation of the innate immune Toll signaling pathway in the larval stage of the genetic model organism Drosophila melanogaster leads to growth failure. Reduced growth caused by active Toll signaling stems from a potent reduction in circulating levels of Drosophila insulin-like peptide 6 (Dilp6), the fly homolog of IGF-1. In this application, genomic and genetic approaches in the mouse and the fruit fly will be used to investigate the negative regulation of animal growth by innate immune and inflammatory signaling. In Aim 1, the molecular mechanisms underlying reduced Dilp6 mRNA levels will be investigated. The principal investigator's lab will determine whether Dif, a homolog of NF-kB, binds directly to the Dilp6 promoter to inhibit its expression and will use a forward genetics approach to find additional transcriptional regulators that contribute to the negative regulation of whole-animal growth and/or Dilp6 downstream of Toll signaling. In Aim 2, molecular mechanisms underlying GH resistance during infection will be investigated. The principal investigator's lab will identify transcriptional mechanisms linking endotoxin and pro-inflammatory cytokine signaling to reduced expression of components of the GH signaling pathway in primary mouse hepatocytes and will use a tissue-specific genetic approach to determine whether MyD88, a common component of the TLR4 and IL-1ß signaling pathways is required in liver to inhibit GH signaling, IGF-1 production and growth in response to Campylobacter infection. Successful completion of the Specific Aims will identify signaling mechanisms underlying a widespread but poorly understood consequence of infection and inflammation: endocrine dysfunction leading to growth failure. The work proposed here will contribute to our understanding of hormone regulation and the control of non-immune functions by innate immune and inflammatory signaling. Furthermore, this work may lead to new therapies for treatment of growth failure and prevention of cognitive impairment in children suffering from chronic infections or inflammatory diseases.

儿童时期的感染和炎症性疾病会导致生长障碍，在世界许多地区，慢性且同时感染多种肠道病原体是这些感染的常见症状，即使他们没有症状。患有炎症性疾病（例如幼年特发性关节炎或克罗恩病）的儿童比健康儿童要小，儿童期生长迟缓与认知能力受损有关。功能障碍是慢性肠道病原体感染儿童和胰岛素样生长因子 1 (Igf1) 基因功能丧失突变患者中常见的一种并发症，导致生长障碍的儿童期感染和炎症性疾病与 IGF 水平低有关。 -1 和生长激素 (GH) 水平升高，表明 GH 抵抗，但导致 GH 的信号事件。对感染和炎症反应的抵抗力尚不清楚。实验室最近发现，遗传模型生物果蝇幼虫阶段先天免疫 Toll 信号通路的激活会导致生长障碍，这是由于活跃的 Toll 信号通路引起的生长减慢源于果蝇胰岛素样循环水平的有效降低。肽 6 (Dilp6)，IGF-1 的果蝇同源物在本应用中，将使用小鼠和果蝇的基因组和遗传学方法来研究先天免疫对动物生长的负调节。在目标 1 中，主要研究人员的实验室将研究 Dilp6 mRNA 水平降低的分子机制，以确定 NF-kB 同源物 Dif 是否直接与 Dilp6 启动子结合以抑制其表达。正向遗传学方法寻找有助于整个动物生长和/或 Toll 信号下游 Dilp6 负调节的额外转录调节因子。在目标 2 中，感染期间 GH 抗性的分子机制将是。首席研究员的实验室将确定内毒素和促炎细胞因子信号转导与原代小鼠肝细胞中 GH 信号转导通路成分表达减少之间的联系，并将使用组织特异性遗传方法来确定 MyD88（一种常见成分）是否存在。肝脏需要 TLR4 和 IL-1ß 信号通路来抑制 GH 信号传导、IGF-1 的产生和生长，以应对弯曲杆菌感染。成功完成特定目标将确定广泛传播的信号传导机制。但对感染和炎症的后果知之甚少：内分泌功能障碍导致生长障碍。这里提出的工作将有助于我们了解先天免疫和炎症信号传导对激素调节和非免疫功能的控制。用于治疗患有慢性感染或炎症性疾病的儿童的生长障碍和预防认知障碍的新疗法。